Perspectives on applying immuno-autonomics to rheumatoid arthritis: results from an online rheumatologist survey.

The term "immuno-autonomics" has been coined to describe an emerging field evaluating the interaction between stress, autonomic nervous system (ANS), and inflammation. The field remains largely unknown among practicing rheumatologists. Our objective was to evaluate the perspectives of rheumatologists regarding the role of stress in the activity and management of rheumatoid arthritis (RA). A 31-item survey was conducted with 231 rheumatologists. Rheumatologists were asked to assess the role of stress in rheumatoid arthritis (RA) disease activity and were provided with information regarding immuno-autonomics. They were asked to consider how immuno-autonomics resonated with their patient management needs. The majority of rheumatologists are eager to better understand non-response, believe that stress biology and ANS dysfunction interfere with disease activity, and embrace the theory that measurement of ANS via next-generation HRV may be able to evaluate autonomic dysfunction and the biology of stress. Rheumatologists are open to the idea that quantitative measurement of ANS function using next-generation HRV can be a helpful tool to RA practice. The majority agree that ANS state influences RA disease control and that quantitative measures of ANS state are helpful to RA practice. Rheumatologists also agree that patients with poor ANS function may be at risk for not responding adequately to conventional, biologic, or targeted synthetic DMARDs. Almost all would use an in-office test to quantitatively measure ANS using next-generation HRV. This study shows that rheumatologists are open to embracing evaluation of ANS function as a possible tool in the management and treatment of RA.

Heart rate variability testing: could it change spending for rheumatoid arthritis patients in the United States? An exploratory economic analysis.

BACKGROUND: Autonomic nervous system (ANS) testing with heart rate variability (HRV) has been shown in early research to predict 52-week outcomes in rheumatoid arthritis (RA). HRV testing could be combined with putative ANS biologic pathways to improve treatment response for RA patients. This study explored potential costs and health outcomes of introducing HRV testing into RA treatment, without and with ANS optimization. METHODS: A decision tree exploratory economic model compared HRV testing to standard care in moderate-to-severe biologic-eligible patients over a 10-year time horizon. HRV data was derived from an observational study of RA patients (n = 33). Patients were stratified into treatment groups based on HRV test scores indicating "low probability of response" and "moderate to high probability of response". This study explored adding ANS optimization based on HRV score followed by clinically-appropriate treatment. Costs and quality-adjusted life-years (QALYs) for the US population were estimated. RESULTS: HRV testing in biologic-eligible patients decreased non-effective biologic use, reducing US healthcare costs by $34.6 billion over 10 years with QALYs unchanged. When combined with ANS optimization in biologic-eligible patients, HRV testing could increase costs by $3.6 billion over 10 years but save over 350,000 QALYs. Among all RA patients, HRV testing with ANS optimization could save over $8 billion and over 100,000 QALYs over 10 years, depending on the positive predictive value (PPV) of the HRV test. CONCLUSIONS: The potential economic impact of introducing HRV testing and ANS optimization into RA treatment appears substantial and cost-effective based on the exploratory analysis. Additional rigorous studies are warranted in larger patient samples to better inform decision-making.

Sodium oxybate reduces pain, fatigue, and sleep disturbance and improves functionality in fibromyalgia: results from a 14-week, randomized, double-blind, placebo-controlled study.

This 14-week, phase 3, double-blind, randomized, controlled trial evaluated sodium oxybate (SXB) 4.5 and 6g per night versus placebo in patients with fibromyalgia (FM). SXB is the sodium salt of γ-hydroxybutyrate (GHB). GHB is an endogenous compound, synthesized from γ-aminobutyric acid (GABA) and found broadly in the central nervous system and body. Among 548 randomized patients, a ≥30% reduction in pain was experienced by 54.2% and 58.5% of patients treated with SXB 4.5 and 6g, respectively, versus 35.2% for placebo with a 100-mm Visual Analog Scale (VAS) (P<0.001 for both comparisons). Relative to placebo, both SXB doses significantly reduced fatigue (with a 100-mm VAS; P<0.001) and sleep disturbance (with the Jenkins Sleep Scale; P<0.001), and resulted in significant improvements in function as measured by the FM Impact Questionnaire (P=0.003 and P=0.001 for 4.5 and 6 g per night, respectively). On the Short-Form 36 Health Survey, SXB-related improvement was significant on the Physical, but not the Mental, Component Scale. The proportion of patients who reported a global improvement of "much" or "very much" better on the Patient Global Impression of Change was significantly greater in both SXB groups versus placebo (P<0.001). Headache, nausea, dizziness, vomiting, diarrhea, anxiety, and sinusitis were the most commonly reported adverse events, with an incidence at least twice that of placebo. These results expand the evidence from previous clinical trials suggesting that SXB is effective and safe in FM.

Patient-derived determinants for participation in placebo-controlled clinical trials for fibromyalgia.

Perspectives of patients with fibromyalgia influence their likelihood of participating in randomized placebo-controlled trials and potentially clash with current, well-established methodology of randomized controlled trial design. Mandates to use only acetaminophen for breakthrough pain and that require discontinuation of concomitant medications, especially in studies lacking an active comparator arm, could bias a trial cohort to thereby reduce the generalizability of study findings and conclusions. This study evaluates factors affecting willingness to participate in such clinical trials, including the impact of altruism, payment, study duration, forced discontinuation of specific medications, and subject demographics for patients seen by rheumatologists proficient and avidly interested in treating fibromyalgia.

Impulse control disorder behaviors associated with pramipexole used to treat fibromyalgia.

OBJECTIVE: Compulsivity has been associated with use of dopamine agonists used to treat Parkinson's disease (PD). Increasing use of these agents to treat fibromyalgia (FM) raises concern for this unexpected toxicity in a new group of patients. This is the first report of compulsive gambling and shopping among patients taking dopamine agonists for treatment of FM. DESIGN: A retrospective chart review of all patients in a large, active FM research practice was used to identify compulsivity associated with dopamine agonists and describe its remission following dug withdrawal. RESULTS: Of 3006 patients with FM treated between 2002 and 2006, 1356 had taken > or =1 dose of a dopamine agonist ( >95% pramipexole). Twenty-one (3 male, 18 female) were identified with compulsive gambling (33%), shopping (40%) or both (27%) after taking a 4.5 mg mean dose of pramipexole at bedtime for 14.4 +/- 14.9 months. Compulsivity resolved in 3-10 days for 19 of 21 patients and by 3 months for all following a monitored, compulsory tapered discontinuation over 7 days. CONCLUSIONS: While biologic aspects of PD and FM differ considerably, compulsive gambling and shopping have become important, yet unexpected concerns related to use of dopamine agonists for patients with FM and their treating clinicians.

Pragmatic consideration of recent randomized, placebo-controlled clinical trials for treatment of fibromyalgia.

A flurry of recent randomized, placebo-controlled trials assessing dissimilar pharmacotherapeutic treatment options for fibromyalgia (FM) have been presented in the past few years. This review evaluates these trials in light of recent pathophysiological concepts germane to FM, including mood disorders, autonomic dysregulation, altered sleep stage architecture, and the diagnostic tender point controversy. Studies with gabapentin, pregabalin, duloxetine, milnacipran, sodium oxybate, and pramipexole for treatment of FM are discussed.

Heart rate variability predicts anti-tumor necrosis factor therapy response for inflammatory arthritis.

To consider autonomic status as a predictor of anti-tumor necrosis factor (TNF) treatment response for inflammatory arthritis, we conducted an exploratory, double-blind, 52-week study with 33 patients with rheumatoid (25) or psoriatic (8) arthritis using heart rate variability (HRV). All were assessed for parasympathetic, sympathetic, total power and tension index measures of autonomic reactivity at initiation of anti-TNF therapy with etanercept (15) or adalimumab (18). Clinical response was assessed at 6, 12, 26 and 52 weeks by internationally accepted outcome criteria (ACR20/50/70 and DAS28 response). Predictive value was demonstrated for all HRV assessments (p-value range 0.001-0.032), except sympathetic (p-value range 0.06-0.22), for ACR20, ACR50 and ACR70 at 52 weeks and at as early as 6 weeks for some measures. Only parasympathetic and tension index predicted DAS28 outcome (p-value range 0.009-0.024). Poor anti-TNF response was associated with low parasympathetic, low total power, high sympathetic and high tension index measures, a profile also predominant in the prior anti-TNF failure subset (12). In conclusion, this unique, exploratory study suggests that HRV may be a novel, useful predictor of response to anti-TNF therapy in patients with inflammatory arthritis, and emphasizes the importance of autonomic influence of autoimmune disease expression.

Positional cervical spinal cord compression and fibromyalgia: a novel comorbidity with important diagnostic and treatment implications.

UNLABELLED: The variable presentation and treatment response of fibromyalgia (FM) may be related to comorbidities, including positional cervical cord compression (PC3). Prevalence of PC3 among routine referrals for rheumatology consultation was assessed over 2 random months (January and February 2006) from a 4-year experience of 1100 patients. PC3 was defined as cord abutment, compression or flattening with a spinal canal diameter of <10 mm by magnetic resonance sagittal flexion, neutral, and extension images. Of 107 referrals, 53 had FM, 32 had a connective tissue disease (CTD) without FM, and 22 had chronic widespread pain (CWP) without FM criteria. The dynamic cervical spine images were obtained in 70 patients: 49 of 53 with FM, 20 of 22 with CWP and 1 of 32 with CTD, based on history and examination. Among those who received magnetic resonance imaging [MRI], 52 patients met PC3 criteria (71% of FM group [35/49], 85% of CWP group [17/20]). Two patients had a Chiari malformation (FM), 1 had multiple sclerosis (CWP), and 1 had multiple myeloma (CWP). Extension views were required for diagnosis for 37 of these 52 (71%) subjects, as well as for 8 patients who also had cervical spinal cord flattening. The pilot data suggest that further evaluation of PC3 in a controlled trial is warranted among patients with FM and CWP. PERSPECTIVE: Fibromyalgia is complex and poorly understood. Recognition of unsuspected, comorbid cervical cord compression may provide new insight into its variable presentation, leading to novel treatment considerations. Also, dissemination of this dynamic MRI protocol may promote further study of this emerging concept of cervical cord irritation.

Novel pharmacotherapy for fibromyalgia.

Fibromyalgia is a common disorder that is characterized by chronic widespread pain, tenderness to light palpation, fatigue and sleep disturbances. The present lack of a well-accepted model of the disorder has hampered progress towards adequate treatment. A review of potential models to explain the pathophysiology underlying its primary symptom (i.e., chronic widespread pain) lends insight on the therapeutic potential of novel therapies. Following this, a mechanistic evaluation of those medications that are under consideration for the treatment of the disorder is offered. Adequate treatment will be likely to involve the identification of biologic subgroups within the greater fibromyalgia construct. Key insights from basic research are the basis for increased optimism for effective relief among patients and clinicians.

A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications.

OBJECTIVE: To assess the efficacy and safety of pramipexole, a dopamine 3 receptor agonist, in patients with fibromyalgia. METHODS: In this 14-week, single-center, double-blind, placebo-controlled, parallel-group, escalating-dose trial, 60 patients with fibromyalgia were randomized 2:1 (pramipexole:placebo) to receive 4.5 mg of pramipexole or placebo orally every evening. The primary outcome was improvement in the pain score (10-cm visual analog scale [VAS]) at 14 weeks. Secondary outcome measures were the Fibromyalgia Impact Questionnaire (FIQ), the Multidimensional Health Assessment Questionnaire (MDHAQ), the pain improvement scale, the tender point score, the 17-question Hamilton Depression Inventory (HAM-d), and the Beck Anxiety Index (BAI). Patients with comorbidities and disability were not excluded. Stable dosages of concomitant medications, including analgesics, were allowed. RESULTS: Compared with the placebo group, patients receiving pramipexole experienced gradual and more significant improvement in measures of pain, fatigue, function, and global status. At 14 weeks, the VAS pain score decreased 36% in the pramipexole arm and 9% in the placebo arm (treatment difference -1.77 cm). Forty-two percent of patients receiving pramipexole and 14% of those receiving placebo achieved > or =50% decrease in pain. Secondary outcomes favoring pramipexole over placebo included the total FIQ score (treatment difference -9.57) and the percentages of improvement in function (22% versus 0%), fatigue (29% versus 7%), and global (38% versus 3%) scores on the MDHAQ. Compared with baseline, some outcomes showed a better trend for pramipexole treatment than for placebo, but failed to reach statistical significance, including improvement in the tender point score (51% versus 36%) and decreases in the MDHAQ psychiatric score (37% versus 28%), the BAI score (39% versus 27%), and the HAM-d score (29% versus 9%). No end points showed a better trend for the placebo arm. The most common adverse events associated with pramipexole were transient anxiety and weight loss. No patient withdrew from the study because of inefficacy or an adverse event related to pramipexole. CONCLUSION: In a subset of patients with fibromyalgia, approximately 50% of whom required narcotic analgesia and/or were disabled, treatment with pramipexole improved scores on assessments of pain, fatigue, function, and global status, and was safe and well-tolerated.

Treatment of fibromyalgia: a changing of the guard.

Fibromyalgia remains one of the most common and enigmatic musculoskeletal disorders among patients with pain and, until recently, few effective treatments have been discovered. This review will briefly consider the rationale supporting traditional treatment options and their efficacy, including the role of exercise and pharmacotherapy. Juxtaposed with these common approaches to relieve fibromyalgia pain and fatigue are the promising new medications that are being developed, such as pregabalin, milnacipran, duloxetine, sodium oxybate, ropinirole and pramipexole. Outcomes from recent randomized trials will be reviewed and compared.